The absence of an effective vaccine for tuberculosis means that TB control relies on the early diagnosis and effective treatment of infectious cases, which is compromised by the relatively low sensitivity and specificity of standard diagnostic tools. Because TB infection most often results in a chronic asymptomatic state, prevention of disease by targeting those who are infected, but not yet ill, has been difficult to implement in high burden settings where more than half of the population is TB infected. The long duration of treatment necessary to achieve high cure rates and the emergence and spread of drug resistant organisms have further undermined the potential impact of national TB control programs. Our proposed plan responds to these research priorities and grows out of a series of recent research findings from our own groups and others that suggest an innovative interdisciplinary approach to the discovery of basic mechanisms through. Our proposed project begins with the identification and longitudinal follow-up of patients diagnosed with active TB and their household contacts. Patients that progress to active TB disease (progressors) are followed for disease outcomes, including relapse, and household contacts are followed for evidence of TB infection and disease. This design and our extensive longitudinal follow up capabilities will allow us to identify and characterize TB index cases and their exposed household contacts through careful clinical and epidemiologic studies, human genomics (by exome sequencing) human genetics (by exome chip), transcriptomics, and metabolomics. We have established Cores in Human subjects, Bio-informatics, and Metabolomics that will work in parallel to identify targets including pathways linking human metabolism and immune response, T cells involved in Mtb response, pathogen determinants of drug resistance and pathogen-shed markers of clinical TB phenotypes. Each project includes validation of these targets in the guinea pig model. Based on our results, we will then go on to test specific interventions in the animal model, focusing in particular on pharmacologic agents that alter human metabolic and immune responses.